Antibody Landscape following Human Norovirus Infection and Vaccination

摘要 人诺如病毒（HuNoV）是急性非细菌性流行性胃肠炎的主要原因， 每年约200，000例死亡，主要发生在婴儿、老年人和免疫抑制人群中。HuNoV疫苗在 但结果是混合的，部分反映了抗原的优先级，病毒的多样性和逃逸。我们 前提是对病毒类型特异性的功能、表位特异性和原子水平的了解， 病毒粒子中广泛交叉的反应性表位引发中和抗体将揭示 保护性体液免疫，这反过来又是设计更有效的免疫原所必需的， 疫苗接种策略。因此，我们的计划旨在批判性地告知广泛的发展， 靶向高度流行的医学上重要的基因组II菌株（GII.4和GII.2）的有效HuNoV疫苗。 为了实现这些目标，我们从接种疫苗的个体队列中获得了相关的时间排序样本集， 自然感染和人类挑战研究，这些研究在整个项目中被用来阐明 控制保护性免疫、病毒逃逸和大流行毒株出现的基本机制。我们 我还召集了一个由著名专家组成的补充小组，以阐明HuNoV中的基本问题 血清学免疫，确定类型特异性和广泛保护性靶向的关键中和表位 免疫，并揭示了HuNoV中和，抗原优先级和广泛的分子机制 保护性免疫此外，该计划旨在将这些新的发现转化为改进的第二代 产生结构引导的HuNoV疫苗免疫原，其被设计为提高免疫应答的广度和 与保护性免疫相关的体液免疫应答的持久性。为了实现这些目标， 该计划有三个具体目标。在目标1中，我们将定义HuNoV特异性血清学抗体库， 生产重组抗体用于详细的结构和分子分析。在目标2中，我们确定了特定类型 广泛交叉中和抗体，并使用分子方法来鉴定关键的相互作用表位。在 目的3：利用衣壳蛋白的P结构域，解析几种相关抗体的原子水平结构 蛋白质来描绘HBGA阻断和中和的结构基础，并使用结构指导的 增加免疫原性宽度和抗原稳定性的策略，导致体内疫苗功能的改善。

Abstract Human noroviruses (HuNoV) are the major cause of acute non-bacterial, epidemic gastroenteritis, resulting in ~200,000 deaths/year, mostly in infant, elderly and immunosuppressed groups. HuNoV vaccines are under development but the results are mixed, in part reflecting antigenic seniority, virus diversity and escape. Our premise is that the function, epitope specificity and atomic level understanding of the virus type specific and broadly cross reactive epitopes in the virion that elicit neutralizing antibody will reveal the mechanisms of protective humoral immunity, which in turn is required for the design of more effective immunogens and vaccination strategies. Consequently, our program is designed to critically inform the development of broadly effective HuNoV vaccines that target highly prevalent, medically important genogroup II strains (GII.4 and GII.2). To achieve these goals, we have relevant time-ordered sample sets from cohorts of vaccinated individuals, natural infections and human challenge studies which are leveraged throughout the program to elucidate the fundamental mechanisms governing protective immunity, virus escape and pandemic strain emergence. We have also assembled a complementary group of renown experts to elucidate the essential issues in HuNoV serological immunity, identify the key neutralizing epitopes targeted by type specific and broadly protective immunity, and reveal the molecular mechanisms governing HuNoV neutralization, antigenic seniority and broad protective immunity. Moreover, the program is designed to translate these novel findings to improved 2nd generation structure-guided HuNoV vaccine immunogens which are designed to improve the breadth and durability of humoral immune responses associated with protective immunity. To achieve these goals, the program has three specific aims. In aim 1, we will define the HuNoV-specific serological antibody repertoire and produce recombinant antibodies for detailed structure and molecular analyses. In aim 2, we identify type specific and broadly cross neutralizing antibodies and use molecular approaches to identify key interacting epitopes. In aim 3, we will solve the atomic level structure of several relevant antibodies with the P domain of the capsid protein to delineate the structural basis for HBGA blockade and neutralization and use structure-guided strategies to increase immunogenic breadth and antigen stability, leading to improved vaccine function in vivo.